Preclinical Detection and Monitoring of Alzheimer’s Disease Using a Multi‐Disease Diagnostic Platform Employing Autoantibodies as Blood‐based Biomarkers

Abstract

AbstractBackgroundEvidence for the universal presence of serum autoantibodies and their potential diagnostic utility for detection of Alzheimer’s disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. It is well known that AD‐related pathological changes in the brain can begin up to a decade before patients experience telltale symptoms, yet preclinical detection remains an unmet goal. In the present study, we demonstrate the utility of a panel of AD‐related autoantibodies capable of detecting AD at the earliest points along the AD continuum, including preclinical AD, years before the onset of symptoms, and prodromal AD (mild cognitive impairment, MCI).MethodUsing a customized panel of AD‐specific autoantibody biomarkers and Luminex xMAP® technology, sera from ADNI subjects with preclinical AD or MCI were screened to demonstrate both preclinical and prodromal AD detection. A panel of eight autoantibodies with increased titer in MCI and preclinical AD relative to controls was evaluated using both Random Forest and Receiver Characteristic Operating curves for their ability to distinguish diseased subjects from age‐ and sex‐matched controls, as well as from individuals with other neurodegenerative and non‐neurodegenerative diseases.ResultResults showed that the panel of eight autoantibody biomarkers was capable of differentiating patients with MCI from corresponding age‐ and sex‐matched controls with high overall accuracy, sensitivity, and specificity. These biomarkers were also capable of identifying cognitively normal subjects who later converted to MCI and AD, years before the clinical onset of their symptoms. This autoantibody biomarker panel readily distinguished MCI and preclinical AD subjects from Parkinson’s disease and breast cancer subjects, demonstrating excellent disease specificity.ConclusionResults demonstrate the utility of our custom Luminex xMAP® blood‐based autoantibody biomarker panel as an accurate, non‐invasive, and inexpensive diagnostic screener, not only for the detection of prodromal AD, but also the earlier stages of pathology, several years before the first onset of telltale clinical symptoms. This appears to be a multi‐disease diagnostic and disease‐staging strategy, since it has been demonstrated to be useful for a multitude of neurodegenerative diseases including both early‐stage AD and PD, as well as Multiple Sclerosis, with other disease applications currently underway